Method for preparing (2s)-1-(2r3s)-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxy benzene-sulphonyl) 3-hydroxy-2,3-dihydro-1h-indole-2-carbonyl pyrrolidine-2-carboxamide

ABSTRACT

An improved process for preparing (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulphonyl)-3-hydroxy-2,3 -dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide by cyclization of (2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl]-(3,4-dimethoxybenzenesulphonyl)amino]acetyl}pyrrolidine-2-carboxamide in the presence of an alkali metal hydroxide in a mixture of polyethylene glycol and water.

This application is a 371 of PCT/FR99/102759 filed Nov. 10, 1999.

The present invention relates to a novel process for the preparation of(2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide,of its solvates and/or of its hydrates.

(2S)-1-[(2R,3S)-5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide,of formula:

hereinafter known as compound A, is to date the most powerful and themost selective nonpeptide antagonist of arginine-vasopressin V_(1a)receptors in various species, in particular of human V_(1a) receptors(C. Serradeil-Le Gal et al., J. Clin. Invest., 1993, 92, 224-231), andis consequently of use in particular in the treatment of ailments of thecardiovascular system, of the central nervous system, of the renalsystem or of the gastric system and as antiemetic or antiproliferativeagent or, in women, for treating dysmenorrhea or premature labor.

The preparation of compound A is illustrated in Patent EP 0 526 348 orU.S. Pat. No. 5,338,755. According to these documents, compound A isprepared by the cyclization reaction, in basic medium, of the compoundof formula:

hereinafter known as compound B.

This reaction, related to an aldolization reaction, results in theformation of the compound of formula:

which, because of the formation of two centers of chirality at the 2-and 3-positions of the 2,3-dihydro-1H-indole ring, is found, at the endof the reaction, in the form of a mixture in the reaction medium of thefour optical isomers.

This mixture is composed of two optical isomers, conventionally referredto as cis isomers, having the H and OH substituents on the same side ofthe ring, and of two optical isomers, conventionally referred to astrans isomers, having the H and OH substituents on either side of thering.

Each of the cis optical isomers is distinguished and characterized inaccordance with the analytical methods and process disclosed in documentEP 0 526 348. An X-ray analysis made it possible to define the absoluteconfiguration of one of the cis optical isomers, that of the other cisoptical isomer being deduced therefrom.

Likewise, each of the trans optical isomers was isolated andcharacterized. However, their absolute configuration was not determined.

Thus, the four optical isomers of the compound of formula (III) have thefollowing physicochemical characteristics and their conventionallyattributed names are shown.

Cis Isomer 1

M.p.=190° C.

α_(D) ²⁰=+115° (c=0.305, chloroform)

absolute configuration.

Cis Isomer 2: Compound A

M.p.=154-162° C.

α_(D) ²⁰=−216° (c=1.0, chloroform)

absolute configuration.

Trans Isomer 1

α_(D) ²⁰=+91° (c=0.03, chloroform)

unattributed absolute configuration.

Trans Isomer 2

M.p.=159° C.

unattributed absolute configuration.

More specifically, the process for the preparation of compound A asdisclosed in the prior art consists in reacting(2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl](3,4-dimethoxybenzene-sulfonyl)amino]acetyl}pyrrolidine-2-carboxamide(compound B) with 1,8-diazabicyclo[5.4.0]undec-7-ene in methanol for 60hours and at a temperature of −10° C. to provide the mixture of the fouroptical isomers of the compound of formula (III).

However, this process has disadvantages, sometimes sufficient to excludeit from any use on the industrial scale.

For example, compound A prepared by this process is obtained with yieldswhich are not very high. During the implementation of this process,compound A has in fact been obtained with final yields of between 12 and20%, calculated from compound B.

One of the main reasons for this low yield is the presence in the mediumof the four optical isomers at the end of the cyclization reaction oncompound B. The content, expressed as % by weight, of each of the fouroptical isomers present in the medium at the end of reactions carriedout under the conditions of the process of the prior art was measured byHigh Performance Liquid Chromatography (HPLC). The mean values are asfollows:

Cis 1 formed Cis 2 formed Trans 1 formed Trans 2 formed (%) compound A(%) (%) (%) 20 40 20 20

These results thus show the not insignificant presence of the cis 1,trans 1 and trans 2 isomers.

Consequently, the separation of compound A from this mixture and thenits purification require numerous stages which contribute, each time, toa decrease in the final yield of compound A.

Furthermore, this process uses 1,8-diazabicyclo[5.4.0]undec-7-ene asbase for carrying out the cyclization, which base is expensive andfurthermore toxic, ruling out its use on the industrial scale.

Finally, implementation of this process requires a very long reactiontime (60 hours).

Consequently, the search for a process for the preparation of compound Awhich does not exhibit the disadvantages and drawbacks of the knownprocess of the prior art is of indisputable interest.

A novel process for the preparation of compound A, by reaction ofcompound B with an alkali metal hydroxide in a polyethylene glycol as amixture with water, which makes it possible to avoid the disadvantagesand drawbacks of the known process of the prior art, has, surprisingly,now been found.

The implementation of the process according to the invention makes itpossible, during the cyclization reaction, to greatly reduce theformation of the cis isomer 1 and to enhance the formation of compoundA. Thus, at the end of the reaction, amounts of the cis isomer 1 of theorder of 0.1 to 7% by weight and amounts of compound A of the order of45 to 60% by weight are achieved.

The separation and the purification of compound A are found to befacilitated thereby and it has been possible to obtain compound A withfinal yields of the order of 35 to 55%, calculated with respect tocompound B.

Furthermore, the process according to the invention employs cheap andnontoxic compounds and makes it possible to greatly reduce the reactiontimes.

According to one of its aspects, a subject matter of the presentinvention is a process for the preparation of(2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide,of its solvates and/or of its hydrates of formula:

by cyclization reaction of(2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl](3,4-dimethoxybenzenesulfonyl)-amino]acetyl}pyrrolidine-2-carboxamideof formula:

characterized in that the cyclization is carried out by an alkali metalhydroxide in a polyethylene glycol with an average molecular weight ofbetween 200 and 600 as a mixture with water.

The polyethylene glycol (PEG) with an average molecular weight ofbetween 200 and 600 used in the above process can be a polyethyleneglycol with a given average molecular weight or alternatively a mixtureof polyethylene glycols with varied average molecular weights.

Preference is given, among polyethylene glycols with an averagemolecular weight of between 200 and 600, to polyethylene glycol 200 or“PEG 200”, polyethylene glycol 400 or “PEG 400”, or polyethylene glycol600 or “PEG 600”.

Preference is particularly given, according to the invention, to the useof polyethylene glycol 400 or “PEG 400”.

The polyethylene glycol/water mixture used in the process of theinvention comprises from 0.1 to 1 volume of water per volume ofpolyethylene glycol. Use is preferably made of a mixture comprising from0.4 to 0.5 volume of water per volume of polyethylene glycol.

The polyethylene glycol/water mixture is used in a proportion of 2 to 10equivalents by volume per equivalent by weight of compound of formula(II). The mixture is preferably used in a proportion of 2 to 5equivalents by volume per equivalent by weight of compound of formula(II).

The alkali metal hydroxide used to carry out the cyclization is chosenfrom sodium hydroxide, potassium hydroxide or lithium hydroxide. Sodiumhydroxide is preferably used.

The alkali metal hydroxide is involved in the reaction in a proportionof 0.1 to 10 molar equivalents per molar equivalent of compound offormula (II), preferably of 0.9 to 1.2 molar equivalents.

The reaction according to the invention is carried out at a temperatureof between 0° C. and 45° C. However, a temperature of between 0° C. andambient temperature (approximately 20 to 25° C.), in particular atemperature of between 0° C. and 17° C., is preferred.

Preferably, at the end of the reaction, the reaction mixture isneutralized, preferably to a pH of between 5.5 and 7.

The neutralization is carried out by addition of an inorganic or organicacid, such as hydrochloric acid, sulfuric acid, potassiumhydrogensulfate or acetic acid, to the reaction mixture, said acidsbeing in solution in water or in water in the presence of awater-miscible solvent, such as an alcohol, for example ethanol, and ata temperature of between 0° C. and ambient temperature (approximatelyfrom 20 to 25° C.).

The process of the invention thus described takes place over a period ofapproximately 0.5 to 7 hours.

This time corresponds, under given operating conditions, to the optimumvalue of the degree of conversion to compound A in the reaction mediumbeing obtained.

It is obvious to a person skilled in the art that this optimum value ofthe degree of conversion to compound A and the time needed for it to beobtained vary according to the chosen operating conditions.

Compound A, thus obtained according to the process of the invention, canbe subsequently separated from the reaction medium according toconventional methods, for example by direct crystallization from thereaction medium after the neutralization stage.

The following nonlimiting examples illustrate the invention. In theseexamples, the controls during or at the end of the reaction were carriedout by HPLC on the reaction medium by taking samples, which areneutralized and diluted in acetonitrile. The results express the contentby weight in % of the various compounds present in the reaction medium.

EXAMPLE 1

The cyclization reactions on compound B by one equivalent of lithiumhydroxide monohydrate at 20° C. in 4 volume of a PEG 400/water mixturein various volume/volume ratios lead, at the end of the reaction, to thefollowing results:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 PEG 400/H₂O Time remainingformed compound A formed formed Impurities (v/v) (min) (%) (%) (%) (%)(%) (%) 60/40 30 0.2 4.9 47.4 18.2 23.0 6.3 70/30 60 0.4 2.8 48.7 16.523.5 8.1 80/20 120  0.1 1.3 45.7 16.7 25.2 11.0 

EXAMPLE 2

The cyclization reactions on compound B by 1 equivalent of lithiumhydroxide monohydrate in 8 volumes of a PEG 400/water (70/30; v/v)mixture at various temperatures lead, at the end of the reaction, to thefollowing results:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 Temperature Time remainingformed compound A formed formed Impurities (° C.) (min) (%) (%) (%) (%)(%) (%)  0 210 0.2 4.7 54.2 12.5 20.2 8.2 13 120 0.9 3.9 49.1 15.1 23.08.0 20  60 0.4 2.8 48.7 16.5 23.5 8.1 40  60 0.1 1.6 46.5 18.6 25.4 7.8

EXAMPLE 3

The cyclization reactions on compound B, at 0° C. or at 15° C., in 8volumes of a PEG 400/water (70/30; v/v) mixture by 1 equivalent ofvarious alkali metal hydroxides lead, at the end of the reaction, to thefollowing results:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 Time remaining formedcompound A formed formed Impurities Base (min) (%) (%) (%) (%) (%) (%)at a temperature of 0° C.: LiOH.H₂O 210 0.2 4.7 54.2 12.5 20.2 8.2 KOH420 0.6 3.3 57.5 11.1 20.9 6.0 NaOH 420 0.5 2.6 60.9 12.1 19.5 4.5 at atemperature of 15° C. LiOH.H₂O 120  0.9 3.9 49.1 15.1 23.0 8.0 KOH 303.2 7.4 43.3 16.6 24.4 5.1 NaOH 30 1.0 5.3 47.9 13.3 27.6 4.9

EXAMPLE 4

Cyclization reactions on compound B by 1 equivalent of sodium hydroxideat 0° C. in 8 volumes of various PEGs as a mixture with water. The baseis dissolved in 1.6 volumes of water and, over 15 minutes, run into thesolution of compound B in the PEG/water (5.6/0.8; v/v) mixtures cooledto 0° C., in each case. The results at the end of the reaction are asfollows:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 Time remaining formedcompound A formed formed Impurities PEG/H₂O (min) (%) (%) (%) (%) (%)(%) PEG 200/H₂O 240 0 2.7 54.1 10.3 22.6 10.3  PEG 400/H₂O 167 0 2.959.0 10.9 21.7 5.5 PEG 600/H₂O 150 0 2.4 54.7 10.8 22.6 9.5

EXAMPLE 5(2S)-1-[(2R,3S)-5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide

32.429 kg of compound B and then 128.0 kg of PEG 400 are charged to ajacketed reactor and left to stir vigorously for 10 minutes at ambienttemperature. 16.5 liters of purified water are then run in and themixture is cooled to 0° C. by circulation of brine in the jacket. Asolution of 2.108 kg of sodium hydroxide pellets in 32.5 liters ofpurified water, cooled beforehand to a temperature of between 15 and 20°C., is subsequently run in slowly and evenly over 1 hour 45 minuteswhile maintaining the temperature of the medium between 0 and 2° C.After the solution has finished being run in, the mixture is left tostir for 15 minutes at a temperature of between 0 and 2° C.

HPLC control gives the following results:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 remaining formed compoundA formed formed Impurities (%) (%) (%) (%) (%) (%) 17.56 4.39 47.12 9.4919.45 1.99

The temperature of the reaction medium is raised to 15-17° C. bycirculation of cold water in the jacket and the mixture is left to stirfor 1 hour at this temperature.

HPLC control shows that the mixture at the end of the reactioncomprises:

Cis 2 Compound B Cis 1 formed Trans 1 Trans 2 remaining formed compoundA formed formed Impurities (%) (%) (%) (%) (%) (%) — 1.01 59.33 13.5325.31 0.82

The pH of the reaction medium is brought to 6, while maintaining thetemperature at 20° C., by running in, over 40 minutes, a solution,cooled beforehand to 20° C., comprising 5.4 kg of a 35% solution ofhydrochloric acid in water, 113.5 liters of water and 211 liters ofethanol denatured with toluene.

The reaction medium is brought to reflux (T=81.1° C.) and left to stirat reflux for 10 minutes. The medium is cooled to 55° C., seeded byaddition of a suspension of 0.391 kg of compound A in 1 liter of waterand maintained at 54-55° C. with minimum stirring for 1 hour. Thetemperature of the medium is gradually brought to 20° C. with a coolinggradient of 10° C./hour and with minimum stirring and then the medium isleft to stir overnight at 20-22° C. The reaction medium is cooled to 10°C., the suspended compound A is filtered off and the product obtained iswashed twice with 32 liters of an ethanol denatured withtoluene/purified water (70/30; v/v) solution and dried under vacuum at80° C.

In this way, 17.860 kg of compound A are obtained in the form of a whitepowder.

Yield: 55.07%

HPLC purity: 99.5%.

What is claimed is:
 1. A process for the preparation of(2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamideof the formula:

or a solvate or hydrate thereof by cyclizing of(2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl](3,4-dimethoxybenzenesulfonyl)amino]acetyl}pyrrolidine-2-carboxamideof the formula:

in the presence of an alkali metal hydroxide in a mixture of water and apolyethylene glycol with an average molecular weight of between 200 and600, wherein the reaction is carried out at a temperature of between 0°C. and 45° C.
 2. A process according to claim 1 wherein the polyethyleneglycol with an average molecular weight of between 200 and 600 is apolyethylene glycol with a given average molecular weight or a mixtureof polyethylene glycols with varied average molecular weights.
 3. Aprocess according to claim 2 wherein the polyethylene glycol with anaverage molecular weight of between 200 and 600 is polyethylene glycol200, polyethylene glycol 400 or polyethylene glycol
 600. 4. A processaccording to claim 3 wherein the polyethylene glycol with an averagemolecular weight of between 200 and 600 is polyethylene glycol
 400. 5. Aprocess according to claim 1 wherein the polyethylene glycol/watermixture comprises from 0.1 to 1 volume of water per volume ofpolyethylene glycol.
 6. A process according to claim 5 wherein thepolyethylene glycol/water mixture comprises from 0.4 to 0.5 volume ofwater per volume of polyethylene glycol.
 7. A process according to claim1 wherein the polyethylene glycol/water mixture is used in a proportionof 2 to 10 equivalents by volume per equivalent by weight of compound offormula (II).
 8. A process according to claim 7 wherein the polyethyleneglycol/water mixture is used in a proportion of 2 to 5 equivalents byvolume per equivalent by weight of compound of formula (II).
 9. Aprocess according to claim 1 wherein the alkali metal hydroxide issodium hydroxide, potassium hydroxide or lithium hydroxide.
 10. Aprocess according to claim 9 wherein the alkali metal hydroxide issodium hydroxide.
 11. A process according to claim 1 wherein the alkalimetal hydroxide is used in a proportion of 0.1 to 10 molar equivalentsper molar equivalent of compound of formula (II).
 12. A processaccording to claim 11 wherein the alkali metal hydroxide is used in aproportion of 0.9 to 1.2 molar equivalents per molar equivalent ofcompound of formula (II).
 13. A process according to claim 1 wherein thereaction is carried out at a temperature of between 0° C. and ambienttemperature.
 14. A process according to claim 13 wherein the reaction iscarried out at a temperature of between 0° C. and 17° C.
 15. A processaccording to claim 1 wherein, at the end of the reaction, the reactionmixture is neutralized to a pH of between 5.5 and
 7. 16. A processaccording to claim 3 wherein the polyethylene glycol/water mixturecomprises from 0.1 to 1 volume of water per volume of polyethyleneglycol.
 17. A process according to claim 16 wherein the polyethyleneglycol/water mixture is used in a proportion of 2 to 10 equivalents byvolume per equivalent by weight of compound of formula (II).
 18. Aprocess according to claim 17 wherein the alkali metal hydroxide issodium hydroxide, potassium hydroxide or lithium hydroxide.
 19. Aprocess according to claim 18 wherein the alkali metal hydroxide is usedin a proportion of 0.1 to 10 molar equivalents per molar equivalent ofcompound of formula (II).
 20. A process according to claim 19 whereinthe reaction is carried out at a temperature of between 0° C. andambient temperature.
 21. A process according to claim 20 wherein, at theend of the reaction, the reaction mixture is neutralized to a pH ofbetween 5.5 and
 7. 22. A process according to claim 4 wherein thepolyethylene glycol/water mixture comprises from 0.4 to 0.5 volume ofwater per volume of polyethylene glycol.
 23. A process according toclaim 22 wherein the polyethylene glycol/water mixture is used in aproportion of 2 to 5 equivalents by volume per equivalent by weight ofcompound of formula (II).
 24. A process according to claim 23 whereinthe alkali metal hydroxide is sodium hydroxide.
 25. A process accordingto claim 24 wherein the alkali metal hydroxide is used in a proportionof 0.9 to 1.2 molar equivalents per molar equivalent of compound offormula (II).
 26. A process according to claim 25 wherein the reactionis carried out at a temperature of between 0° C. and 17° C.
 27. Aprocess according to claim 26 wherein, at the end of the reaction, thereaction mixture is neutralized to a pH of between 5.5 and 7.